Preclinical and clinical studies suggest that inflammation and vascular dysfunction contribute to the pathogenesis of major depressive disorder (MDD). Chronic social stress alters blood-brain barrier (BBB) integrity through loss of tight junction protein claudin-5 (cldn5) in male mice, promoting passage of circulating proinflammatory cytokines and depression-like behaviors. This effect is prominent within the nucleus accumbens, a brain region associated with mood regulation; however, the mechanisms involved are unclear. Moreover, compensatory responses leading to proper behavioral strategies and active resilience are unknown. Here we identify active molecular changes within the BBB associated with stress resilience that might serve a protective role for the neurovasculature. We also confirm the relevance of such changes to human depression and antidepressant treatment. We show that permissive epigenetic regulation of cldn5 expression and low endothelium expression of repressive cldn5-related transcription factor foxo1 are associated with stress resilience. Region- and endothelial cell-specific whole transcriptomic analyses revealed molecular signatures associated with stress vulnerability vs. resilience. We identified proinflammatory TNFα/NFκB signaling and hdac1 as mediators of stress susceptibility. Pharmacological inhibition of stress-induced increase in hdac1 activity rescued cldn5 expression in the NAc and promoted resilience. Importantly, we confirmed changes in HDAC1 expression in the NAc of depressed patients without antidepressant treatment in line with CLDN5 loss. Conversely, many of these deleterious CLDN5-related molecular changes were reduced in postmortem NAc from antidepressant-treated subjects. These findings reinforce the importance of considering stress-induced neurovascular pathology in depression and provide therapeutic targets to treat this mood disorder and promote resilience.

中文翻译：

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血脑屏障的分子适应可促进压力恢复能力和抑郁症的抵抗力。


临床前和临床研究表明，炎症和血管功能障碍是重度抑郁症（MDD）的发病机制之一。慢性社会压力会通过雄性小鼠紧密连接蛋白claudin-5 (cldn5) 的丧失来改变血脑屏障 (BBB) 的完整性，从而促进循环促炎细胞因子的通过和抑郁样行为。这种效应在伏隔核中尤为突出，伏隔核是与情绪调节相关的大脑区域。然而，所涉及的机制尚不清楚。此外，导致适当行为策略和积极弹性的补偿反应尚不清楚。在这里，我们确定了血脑屏障内与应激恢复相关的活跃分子变化，这可能对神经血管系统起到保护作用。我们还证实了这种变化与人类抑郁症和抗抑郁治疗的相关性。我们发现 cldn5 表达的允许表观遗传调控和抑制性 cldn5 相关转录因子 Foxo1 的低内皮表达与应激恢复相关。区域和内皮细胞特异性全转录组分析揭示了与应激脆弱性与恢复力相关的分子特征。我们确定促炎性 TNFα/NFκB 信号传导和 hdac1 作为应激敏感性的介质。对应激诱导的 hdac1 活性增加的药理学抑制可挽救 NAc 中的 cldn5 表达并促进恢复力。重要的是，我们证实了未经抗抑郁治疗的抑郁症患者 NAc 中 HDAC1 表达的变化与 CLDN5 缺失一致。相反，在接受抗抑郁药治疗的受试者死后 NAc 中，许多与 CLDN5 相关的有害分子变化有所减少。 这些发现强调了在抑郁症中考虑压力诱发的神经血管病理学的重要性，并为治疗这种情绪障碍和促进恢复力提供了治疗目标。